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Pamiparib Induces Neurodevelopmental Defects and Cerebral Haemorrhage in Zebrafish Embryos via Inhibiting Notch Signalling

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Abstract

Pamiparib is a poly ADP-ribose polymerase (PARP) inhibitor used in clinical studies, which can penetrate the blood–brain barrier efficiently. At present, there are few studies on its effect on vertebrate neurodevelopment. In this study, we exposed zebrafish embryos to 1, 2 and 3 µM of Pamiparib from 6 to 72 h post-fertilisation (hpf). Results showed that pamiparib can specifically induce cerebral haemorrhage, brain atrophy and movement disorders in fish larvae. In addition, pamiparib exposure leads to downregulation of acetylcholinesterase (AChE) and adenosine triphosphate (ATPase) activities, and upregulation of oxidative stress which then leads to apoptosis and disrupts the gene expression involved in the neurodevelopment, neurotransmitter pathways and Parkinson’s disease (PD) like symptoms. Meanwhile, astaxanthin can partially rescue neurodevelopmental defects by downregulating oxidative stress. After exposure to pamiparib, the Notch signalling is downregulated, and the use of an activator of Notch signalling can partially rescue neurodevelopmental toxicity. Therefore, our research indicates that pamiparib may induce zebrafish neurotoxicity by downregulating Notch signalling and provides a reference for the potential neurotoxicity of pamiparib during embryonic development.

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Data Availability

All data generated or analysed during this study are included in this article and its supplementary materials.

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Acknowledgements

The authors thank all the subjects for their participation in the study.

Funding

This work was supported by the National Natural Science Foundation (31900597, 81860282, 81960101); Natural Science Foundation Project of Jiangxi Province (20192ACB21013); Jiangxi Province’s major academic and technical leaders training plan for young talents (20204BCJL23043); and Jiangxi Provincial Department of Education Science and Technology Program Project (GJJ211004).

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Authors and Affiliations

  1. Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs, College of Life Sciences, Jinggangshan University, Ji’an, 343009, Jiangxi, China

    Dou Yang, Fasheng Liu, Mengqi Wan, Jieping Liu, Ling Huang, Chao Chen, Xue Li, Li Zhang, Xinjun Liao, Guanghua Xiong, Huiqiang Lu & Zigang Cao

  2. College of Pharmacy, Nanchang University, Nanchang, 330027, Jiangxi, China

    Dou Yang

  3. Affiliated Hospital of Jinggangshan University, Ji’an, 343000, Jiangxi Province, China

    Xiaobing Ding

  4. Department of Ultrasound, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang University, Nanchang, 330006, Jiangxi, China

    Juhua Xiao

Authors
  1. Dou Yang
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  2. Fasheng Liu
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  3. Mengqi Wan
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  4. Jieping Liu
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  8. Li Zhang
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  11. Guanghua Xiong
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  14. Zigang Cao
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Contributions

Z.C. and D.Y. designed experiment and wrote the manuscript; D.Y. performed all of experiments; F.L., M.W., J.L., L.H.,C.C., X.L.,L.Z.,X.D., X.L.,G.X., H.L,J.X., and Z.C. analysed data.

Corresponding author

Correspondence to Zigang Cao.

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Ethics Approval

All fish were raised and maintained under standard laboratory conditions in accordance with the Guidelines of Experimental Animal Welfare from Ministry of Science and Technology of People’s Republic of China (2006) and the Institutional Animal Care and Use Committee protocols from Jinggangshan University (2016).

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Yang, D., Liu, F., Wan, M. et al. Pamiparib Induces Neurodevelopmental Defects and Cerebral Haemorrhage in Zebrafish Embryos via Inhibiting Notch Signalling. Mol Neurobiol 59, 6652–6665 (2022). https://doi.org/10.1007/s12035-022-02988-z

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